Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis
Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis
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DOI：
10.1182/blood-2010-05-284737
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发表时间：
2011-01-13
期刊：
影响因子：
20.3
通讯作者：
Uchiyama, Takashi
中科院分区：
文献类型：
--
作者：
Hirai, Makiko;Kadowaki, Norimitsu;Uchiyama, Takashi
树突状细胞在炎症性疾病的发病机制中起着关键作用，因此抑制树突状细胞的活性有助于治疗这类疾病。在本研究中，我们发现一种蛋白酶体抑制剂硼替佐米通过靶向2个临界点，即核酸敏感toll样受体（TLRs）的细胞内运输和内质网（ER）稳态，抑制人浆细胞样DCs （pDCs）的存活和免疫刺激功能。在血液中的免疫细胞中，pDCs对硼替佐米的杀伤作用最敏感。这与转录因子XBP1剪接形式的减少有关，XBP1通过维持内质网稳态来拯救细胞免于凋亡。硼替佐米抑制了由刺激tlr9的CpG DNA和刺激tlr7的流感病毒激活的pDCs产生的干扰素- α和白细胞介素-6，这似乎部分独立于细胞凋亡。硼替佐米抑制TLR9从内质网转运到内溶酶体，但不抑制将TLR9转运到内溶酶体的内质网膜蛋白Unc93B1。因此，硼替佐米通过破坏tlr和Unc93B1的协调易位以及扰乱内质网稳态来抑制tlr的细胞内运输，从而抑制pDCs的活性。这项研究表明，蛋白酶体抑制剂可能减轻炎性疾病，如狼疮和牛皮癣，涉及pDCs。（血液，2011;117(2):500-509）
Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensing Toll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-alpha and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs. (Blood. 2011; 117(2):500-509)